The cytotoxic T cell (CTL) specifically recognizes and kills by direct lysis target cells which are diseased or foreign. CTL recognition is advantageous to the host when the target cells are malignantly transformed or virally infected and nonadvantageous to the host when the target cells are from transplanted or self tissue. The clinical benefits of manipulating the CTL response are clear. This will require a thorough understanding of CTL activation and recognition. The generation of a CTL response involves the interaction of several cell types: pre-CTL, T-helper cells (TH), and antigen-presenting cells (APC). The aim of this project is to more precisely define the interactions involved in generating the CTL response to class I major histocompatibility complex (MHC) antigens. Class I MHC antigens are used because purified antigen can be inserted in liposomes and used to stimulate a CTL response. Use of this antigen will allow biochemical and genetic manipulation of the antigen to assess the specificity requirements for T-cell recognition. These experiments will determine the role of antigen processing by a variety of cell types in the presentation of class I MHC antigens. Primed splenic T cells and T-cell hybridomas will be used to compare the ability of cloned CTL and TH with primed T-cell populations. The ability of T cells to recognize native antigen will be assayed by the ability of a panel of anti-H-2 antibodies to inhibit recognition. Antibodies to T-cell surface markers will be used to determine the role of accessory molecules in T-cell activation. Defining the requirements for the generation of a CTL response will clarify the pathway for clinical intervention in the CTL response. (CS)